“消炎良境”铂药纳米制剂增强免疫治疗转移性结直肠癌的研究

结直肠癌生存期短，是临床危重病症之一。复杂的炎性病理特性使其易发生转移，而现有化疗联合分子靶向治疗策略存在选择性差、耐药性快等问题。在前期研究基础上，本项目拟构建一种“消炎良境”铂药纳米制剂增强免疫疗法新模式，用聚哌啶包载抗炎铂前药，同时嵌入脂质化归巢肽。借助聚乙二醇长循环作用和趋向肽归巢效应，靶向递送抗炎铂前药至肿瘤组织；胞内响应释放的奥沙利铂活性成分抗增殖，诱导核仁应激和免疫原性细胞死亡；释放的非甾体抗炎药抑制炎症酶环氧化酶-2，下调抗凋亡蛋白增强抗增殖，亦下调转移相关蛋白阻止肿瘤转移，还可降低炎症因子水平解除免疫抑制，实现“消炎良境”目的。再联合免疫检查点抑制剂解除免疫抑制，多方面解除免疫抑制增强杀伤性T细胞浸润和杀伤功能。本项目针对结直肠癌复杂的炎性病理微环境，构建“消炎良境”双功能铂前药纳米制剂，实现消炎增强免疫疗法全方位多途径发挥抗增殖和抗转移，为转移性结直肠癌治疗提供新策略。

Metastatic colorectal cancer has a short survival time and is one of the clinically severe diseases. The complicated inflammatory pathological characteristics make it easy to metastasize, which leads to some problems such as the poor clinical efficacy of clinical chemotherapy strategy and rapid drug resistance of molecular targeted drugs. Based on previous research, this project proposes a new treatment strategy that "anti-inflammatory for improved microenvironment" platinum prodrug nano-formulation enhances immunotherapy. Polypiperidine is used to encapsulate anti-inflammatory platinum prodrugs while embedding lipidated homing peptides. This nano-formulation can effectively deliver the anti-inflammatory platinum prodrugs to tumor tissues through the long-term effects of polyethylene glycol and the homing effect of peptide. And then the intracellular pH-responsive released oxaliplatin active component is anti-proliferative, induces nucleolar stress and triggers immunogenic cell death. The released non-steroidal anti-inflammatory drugs inhibit the inflammatory enzyme cyclooxygenase-2, down-regulate anti-apoptotic proteins to enhance anti-proliferation, and also down-regulate metastasis-associated protein to suppress tumor metastasis, and can also reduce the level of inflammatory factors to relieve immune suppression. These results can achieve the purpose of "anti-inflammatory for improved microenvironment". The immune checkpoint inhibitor was combined to further relieve immunosuppression, which achieves a variety of relieving immunosuppression and enhances killer T cell infiltration and killing function. This project aims at the complex inflammatory pathological microenvironment of colorectal cancer, and constructs an "anti-inflammatory for improved microenvironment" bifunctional platinum prodrug nano-formulation to realize anti-inflammatory and enhanced immunotherapy in all aspects. It can exert anti-proliferation and metastasis effects in all aspects and provide an effective new strategy for drug treatment for tumor metastasis.